Activation of opioid mu receptors in caudal medullary raphe region inhibits the ventilatory response to hypercapnia in anesthetized rats

Anesthesiology. 2007 Aug;107(2):288-97. doi: 10.1097/01.anes.0000270760.46821.67.


Background: : Opioids, extensively used as analgesics, markedly depress ventilation, particularly the ventilatory responsiveness to hypercapnia in humans and animals predominantly via acting on mu receptors. The medullary raphe region (MRR) contains abundant mu receptors responsible for analgesia and is also an important central area involving carbon dioxide chemoreception and contributing to the ventilatory responsiveness to hypercapnia. Therefore, the authors asked whether activation of mu receptors in the caudal, medial, or rostral MRR depressed ventilation and the response to hypercapnia, respectively.

Methods: : Experiments were conducted in 32 anesthetized and spontaneously breathing rats. Ventilation and it response to progressive hypercapnia were recorded. The slopes obtained from plotting minute ventilation, respiratory frequency, and tidal volume against the corresponding levels of end-tidal pressure of carbon dioxide were used as the indices of the respiratory responsiveness to carbon dioxide. DAMGO ([d-Ala2, N-Me-Phe4, Gly-ol]-enkephalin), a mu-receptor agonist, was systemically administered (100 mug/kg) before and/or after local injection of CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) (100 ng/100 nl), a mu-receptor antagonist, into the caudal MRR, or locally administered (35 ng/100 nl) into the MRR subnuclei.

Results: : The authors found that systemic DAMGO significantly inhibited ventilation and the response to carbon dioxide by 20% and 31%, respectively, and these responses were significantly diminished to 11% and 14% after pretreatment of the caudal MRR with CTAP. Local administration of DAMGO into the caudal MRR also reduced ventilation and the response to carbon dioxide by 22% and 28%, respectively. In sharp contrast, these responses were not observed when the DAMGO microinjection was made in the middle MRR or rostral MRR.

Conclusions: : These results lead to the conclusion that mu receptors in the caudal MRR rather than the middle MRR or rostral MRR are important but not exclusive for attenuating the hypercapnic ventilatory response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Anesthesia / methods
  • Animals
  • Carbon Dioxide / metabolism
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology*
  • Hypercapnia*
  • Male
  • Medulla Oblongata / drug effects
  • Medulla Oblongata / physiology*
  • Narcotic Antagonists / pharmacology
  • Peptide Fragments
  • Peptides / pharmacology
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / metabolism*
  • Respiratory Physiological Phenomena / drug effects*
  • Somatostatin
  • Time Factors


  • Analgesics, Opioid
  • CTAP octapeptide
  • Narcotic Antagonists
  • Peptide Fragments
  • Peptides
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Carbon Dioxide
  • Somatostatin